1. Field of the Invention
The present invention relates to crystalline etoposide 4'-phosphate diethanol solvate.
2. Background Art
Etoposide is an anticancer agent currently approved in the United States for the treatment of small cell lung cancer and refractory testicular tumor. Because etoposide is only sparingly soluble in water, an organic solvent or a mixture of organic solvents is required to prepare etoposide solution. The etoposide product for parenteral administration currently being marketed is contained in a multi-solvent system.
Etoposide 4'-phosphate (I) and its disodium salt (II) are disclosed in U.S. Pat. No. 4,904,768 as prodrug forms of etoposide, and have been shown to be as active as etoposide in in vivo antitumor assays. ##STR1## Whereas the solubility of etoposide in water is about 0.1 mg/ml, both etoposide 4'-phosphate and its disodium salt exhibit water solubility of .gtoreq.100 mg/ml thereby allowing the preparation of pharmaceutical formulations with little or no organic solvents. The previously disclosed forms of etoposide 4'-phosphate and its disodium salt are fluffy, amorphous materials which are difficult to handle and tend to decompose upon storage. Thus, one object of the present invention is to provide a form of etoposide 4'-phosphate that may be more advantageously used than the earlier forms for pharmaceutical purposes. The present invention concerns a novel crystalline ethanol solvate of etoposide 4'-phosphate which is easier to handle and exhibits unexpected stability compared to the known forms of etoposide 4'-phosphate.